Genetic Predictors of Resistance and Survival in Oxaliplatin-Treated Iraqi Patients with Colorectal Cancer

Background: Resistance to oxaliplatin-based chemotherapy critically limits treatment efficacy in colorectal cancer (CRC), a leading cause of cancer mortality. While GSTP1 polymorphisms have been studied in other ethnic groups, their impact remains unclear in Middle Eastern populations. Objective: To evaluate the association of GSTP1 rs1695 and rs1138272 polymorphisms with treatment resistance and survival outcomes in Iraqi CRC patients undergoing oxaliplatin-based chemotherapy, considering relevant clinical variables. Methods: A prospective cohort of 120 Iraqi CRC patients was followed for 12 months. Genotyping for GSTP1 variants was performed using PCR and Sanger sequencing. Clinical data, chemotherapy protocols, and survival metrics were collected. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were estimated using Cox regression models. Results: Univariate analysis revealed significant risk factors for progression: liver metastasis (HR=2.19), palliative chemotherapy (HR=1.94), elevated baseline CEA (HR=1.77), and FOLFOX+ bevacizumab treatment (HR=3.78). The GSTP1 rs1695 AG (HR=0.28) and GG (HR=0.18) genotypes showed protective effects. In multivariate analysis, the rs1695 GG genotype independently predicted reduced progression (HR=0.42) and mortality (HR=0.25). FOLFOX-based regimens, especially with bevacizumab, were associated with worse outcomes than XELOX. Grade 2 neurotoxicity correlated with longer PFS. Conclusions: The GSTP1 rs1695 GG genotype is associated with improved survival and reduced progression in oxaliplatin-treated CRC patients, while FOLFOX-based regimens may confer a higher risk. Genotyping GSTP1 may support individualized therapy optimization.